The major goals of our studies are to define defects in lymphocyte differentiation or function that are associated with immune deficiency diseases, lymphoid malignancies, and disorders of immunoregulation. Our thesis is that gaps in knowledge about the human immune system can be addressed best by the comparative analysis of the normal ontogeny of the immune system and a variety of patients with immune system dysfunction. The present emphasis of our studies is on (1) the ontogeny of B cell development in humans, (2) the genetic basis of immunodeficiency, and (3) the influence of gene defects on the differentiation and function of immunocompetent cells. In the last few years we have obtained evidence indicating that a genetic link exists between the two most common primary immunodeficiency diseases, IgA deficiency (IgAD) and common variable immunodeficiency (CVID). Genetic susceptibility for developing IgAD or CVID in a large subgroup of these patients seems to be associated with a gene or genes located in the class III MHC region. The disease phenotype and prevalence of immunodeficiency in the offspring of these patients differ in the individuals who lack the susceptibility MHC haplotype. We plan to continue the analysis of MHC haplotypes in these patients and their families to elucidate which gene in the MHC region is associated with these diseases. More recently we have identified a population of memory B cells that is acquired as a function of age in bone marrow. We are further characterizing this subset of B cells in normal bone marrow samples. In addition we are examining the hypothesis that this population of memory B cells may not be acquired normally in CVID patients. Preliminary results in 5 individuals with CVID suggest an arrest in the progression of memory B cell activation.